The field of the invention is modulation of drug resistance.
The concentrations of proteins in biological cells are regulated by elegant biochemical mechanisms. By way of these mechanisms, cells eliminate damaged proteins and can, by altering the concentrations of biologically active proteins, such as enzymes, alter cellular processes that are important for the overall well being of the organism.
In eukaryotic cells, proteins can be selectively degraded via the ubiquitin pathway. Ubiquitin is a highly conserved protein that is covalently ligated to proteins in a process referred to as ubiquitination. Proteins that have been ubiquitinated are committed to degradation by a 26S protease complex. The ubiquitin pathway is thought to play an important role in regulating cellular processes by regulating protein levels. Numerous review articles have described various aspects of the ubiquitin pathway. For example, the molecular genetics of the ubiquitin system have been reviewed by Finley et al. (Ann. Rev. Cell Biol. 7:25-69, 1991) and Jentsch et al. (Biochim. Biophys. Acta 1089:127-139, 1991); the involvement of the system in pathological states has been reviewed by Mayer et al. (Biochim. Biophys. Acta 1089:141-157, 1991); and the biochemistry and enzymology of various stages of the ubiquitin pathway have been reviewed by Hershko and Ciechanover (Ann. Rev. Biochem. 61:761-807, 1992). Interest in the ubiquitin pathway is due in part to the wide variety of physiological processes that are affected by ubiquitination of proteins. These processes include the heat shock response, DNA repair, cell cycle progression, the modification of histones and of receptors, and the possible pathogenesis of selected neurodegenerative diseases.
Only the protein conjugated to ubiquitin is degraded via the proteasome; ubiquitin itself is recycled by ubiquitin carboxy-terminal hydrolases, which cleave the bond between ubiquitin and the protein targeted for degradation. These enzymes constitute a family of thiol proteases, and homologues have been found in, for example, yeast (Miller et al., BioTechnology 7:698-704, 1989; Tobias and Varshavsky, J. Biol. Chem. 266:12021-12028, 1991; Baker et al., J. Biol. Chem. 267:23364-23375, 1992), bovine (Papa and Hochstrasser, Nature 366:313-319, 1993), avian (Woo et al., J. Biol. Chem. 270:18766-18773, 1995), Drosophila (Zhang et al., Dev. Biol. 17:214, 1993) and human (Wilkinson et al., Science 246:670, 1989) cells.